Astonishingly little information exists about oligodendrocyte development in the normally developing human brain. Despite the body of knowledge assembled from work conducted in animal models, the primary question of how these observations relate to human oligodendrocyte development remains unanswered. Further, elucidation of this sequence specifically in human brain will provide insight into the relation between prenatal and neonatal disturbances of this process and both acquired and dysgenetic abnormalities of brain observed in the human infant. The hypotheses to be evaluated by the proposed research are: 1.) a progenitor cell in perinatal human brain responds to environmental cues to become a mature oligodendrocyte which first appears at a characteristic time in brain development; 2.) the insulin-like growth factors (IGF-1, IGF-2) help direct human oligodendroglial differentiation in an autocrine or paracrine manner; and 3.) the IGFs play a regulating role in a terminal step of human oligodendroglial development involving programmed cell death (apoptosis). To test these hypotheses, we will identify the human oligodendrocyte differentiation sequence in tissue culture obtained from human fetal brain by employing immunohistochemical techniques to detect specific cell markers of oligodendroglial maturation. The sources and effects of IGF-1 and -2 upon oligodendrocyte differentiation will be discerned with RNA techniques, including northern blot, S1 nuclease hybridization and anti-sense oligonucleotide translation blocking. Finally, the role of the IGFs in apoptosis of the nascent human oligodendrocyte population will be investigated in vitro,at the levels of chromosomal integrity, transcription, translation and cell morphology. These studies will provide crucial information about human oligodendroglial differentiation from human brain which will permit direct inquiry to be made concerning how disturbances of this process can result in congenital and acquired lesion of white matter found in the human infant.